Peng Jiangling, Miller Mark, Li Bingbing X, Xiao Xiangshu
Department of Chemical Physiology and Biochemistry, Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
ACS Med Chem Lett. 2022 Feb 17;13(3):388-395. doi: 10.1021/acsmedchemlett.1c00499. eCollection 2022 Mar 10.
cAMP-response element binding protein (CREB) is a transcription factor involved in multiple cancers. Chemical inhibitors of CREB represent potential anticancer agents. We previously identified as a potent CREB inhibitor. While showed efficacious anticancer activity in vivo through intraperitoneal (IP) injection, its oral bioavailability is limited. To increase its oral bioavailability, we describe synthesis and evaluation of prodrugs based on . The amino acid esters were attempted, but they were not stable for detailed characterization. The corresponding sulfate and phosphates were prepared. The sulfate of was too stable to release while the phosphates were converted into with half-lives of ∼2 h. Phosphate was also a potent CREB inhibitor with anti-breast cancer activity. Furthermore, compound showed much improved oral bioavailability at 38%. These studies support that can be used as an oral CREB inhibitor while IP administration of is preferred for in vivo applications.
环磷酸腺苷反应元件结合蛋白（CREB）是一种涉及多种癌症的转录因子。CREB的化学抑制剂代表了潜在的抗癌药物。我们之前鉴定出[具体物质]作为一种有效的CREB抑制剂。虽然[具体物质]通过腹腔注射在体内显示出有效的抗癌活性，但其口服生物利用度有限。为了提高其口服生物利用度，我们描述了基于[具体物质]的前药的合成与评估。尝试了氨基酸酯，但它们不稳定，无法进行详细表征。制备了相应的硫酸盐和磷酸盐。[具体物质]的硫酸盐过于稳定，无法释放[具体物质]，而磷酸盐转化为[具体物质]的半衰期约为2小时。磷酸酯[具体物质]也是一种具有抗乳腺癌活性的有效CREB抑制剂。此外，化合物[具体物质]的口服生物利用度提高到了38%，有了很大改善。这些研究表明，[具体物质]可用作口服CREB抑制剂，而在体内应用时，腹腔注射[具体物质]更为可取。
